1. Field of the Invention
The present invention relates generally to therapeutic expandable stent prosthesis for implantation in body lumens, e.g., vascular implantation and, more particularly, to a process for providing biostable elastomeric coatings on such stents which incorporate biologically active species having controlled release characteristics directly in the coating structure.
2. Related Art
In surgical or other related invasive medicinal procedures, the insertion and expansion of stent devices in blood vessels, urinary tracts or other difficult to access places for the purpose of preventing restenosis, providing vessel or lumen wall support or reinforcement and for other therapeutic or restorative functions has become a common form of long-term treatment. Typically, such prosthesis are applied to a location of interest utilizing a vascular catheter, or similar transluminal device, to carry the stent to the location of interest where it is thereafter released to expand or be expanded in situ. These devices are generally designed as permanent implants which may become incorporated in the vascular or other tissue which they contact at implantation.
One type of self-expanding stent has a flexible tubular body formed of several individual flexible thread elements each of which extends in a helix configuration with the centerline of the body serving as a common axis. The elements are wound in a common direction, but are displaced axially relative to each other and meet, under crossing a like number of elements also so axially displaced, but having the opposite direction of winding. This configuration provides a resilient braided tubular structure which assumes stable dimensions upon relaxation. Axial tension produces elongation and corresponding diameter contraction that allows the stent to be mounted on a catheter device and conveyed through the vascular system as a narrow elongated device. Once tension is relaxed in situ, the device at least substantially reverts to its original shape. Prosthesis of the class including a braided flexible tubular body are illustrated and described in U.S. Pat. Nos. 4,655,771 and 4,954,126 to Wallsten and U.S. Pat. No. 5,061,275 to Wallsten et al.
Implanted stents have also been used to carry medicinal agents, such as thrombolytic agents. U.S. Pat. No. 5,163,952 to Froix discloses a thermal memoried expanding plastic stent device which can be formulated to carry a medicinal agent by utilizing the material of the stent itself as an inert polymeric drug carrier. Pinchuk, in U.S. Pat. No. 5,092,877, discloses a stent of a polymeric material which may be employed with a coating associated with the delivery of drugs. Other patents which are directed to devices of the class utilizing bio-degradable or bio-sorbable polymers include Tang et al, U.S. Pat. No. 4,916,193, and MacGregor, U.S. Pat. No. 4,994,071. Sahatjian in U.S. Pat. No. 5,304,121, discloses a coating applied to a stent consisting of a hydrogel polymer and a preselected drug; possible drugs include cell growth inhibitors and heparin. A further method of making a coated intravascular stent carrying a therapeutic material in which a polymer coating is dissolved in a solvent and the therapeutic material dispersed in the solvent and the solvent thereafter evaporated is described in Berg et al, U.S. Pat. No. 5,464,650, issued Nov. 5, 1995 and corresponding to European patent application 0 623 354 A1 published Nov. 9, 1994.
An article by Michael N. Helmus (a co-inventor of the present invention) entitled xe2x80x9cMedical Device Designxe2x80x94A Systems Approach: Central Venous Cathetersxe2x80x9d, 22nd International Society for the Advancement of Material and Process Engineering Technical Conference (1990) relates to polymer/drug/membrane systems for releasing heparin. Those polymer/ drug/membrane systems require two distinct layers to function.
The above cross-referenced grandparent application supplies an approach that provides long-term drug release, i.e., over a period of days or even months, incorporated in a controlled-release system. The parent application and present invention provide a process for coating such stents including techniques that enable the initial burst effect of drug elation to be controlled and the drug release kinetic profile associated with long-term therapeutic effect to be modified.
Metal stents of like thickness and weave generally have better mechanical properties than polymeric stents. Metallic vascular stents braided of even relatively fine metal filament can provide a large amount of strength to resist inwardly directed circumferential pressure in blood vessels. In order for a polymer material to provide comparable strength characteristics, a much thicker-walled structure or heavier, denser filament weave is required. This, in turn, reduces the cross-sectional area available for flow through the stent and/or reduces the relative amount of open space available in the structure. In addition, when applicable, it is usually more difficult to load and deliver polymeric stents using vascular catheter delivery systems.
It will be noted, however, that while certain types of stents such as braided metal stents may be superior to others for some applications, the process of the present invention is not limited in that respect and may be used to coat a wide variety of devices. The present invention also applies, for example, to the class of stents that are not self-expanding including those which can be expanded, for instance, with a balloon. Polymeric stents, of all kinds can be coated using the process. Thus, regardless of particular detailed embodiments the use of the invention is not considered or intended to be limited with respect either to stent design or materials of construction. Further, the present invention may be utilized with other types of implant prostheses.
Accordingly, it is a primary object of the present invention to provide a coating process for coating a stent to be used as a deployed stent prosthesis, the coating being capable of long-term delivery of biologically active materials.
Another object of the invention is to provide a process for coating a stent prosthesis using a biostable hydrophobic elastomer in which biologically active species are incorporated within a cured coating.
Still another object of the present invention is to provide a multi-layer coating in which the percentage of active material can vary from layer to layer.
A further object of the present invention is to control or modify aspects of the timed or time variable drug delivery from a stent coating by controlling average particle size in the biologically active species.
Other objects and advantages of the present invention will become apparent to those stilled in the art upon familiarization with the specification and appended claims.
The present invention provides processes for producing a relatively thin layer of biostable elastomeric material in which an amount of biologically active material is dispersed as a coating on the surfaces of a deployable stent prosthesis. The preferred stent to be coated is a self-expanding, open-ended tubular stent prosthesis. Although other materials, including polymer materials, can be used, in the preferred embodiment, the tubular body is formed of an open braid of fine single or polyfilament metal wire which flexes without collapsing and readily axially deforms to an elongate shape for transluminal insertion via a vascular catheter. The stent resiliently attempts to resume predetermined stable dimensions upon relaxation in situ.
The coating is preferably applied as a mixture, solution or suspension of polymeric material and finely divided biologically active species dispersed in an organic vehicle or a solution or partial solution of such species in a solvent or vehicle for the polymer and/or biologically active species. For the purpose of this application, the term xe2x80x9cfinely dividedxe2x80x9d means any type or size of included material from dissolved molecules through suspensions, colloids and particulate mixtures. The active material is dispersed in a carrier material which may be the polymer, a solvent, or both. The coating is preferably applied as a plurality of relatively thin layers sequentially applied in relatively rapid sequence and is preferably applied with the stent in a radially expanded state. In some applications the coating may further be characterized as a composite initial tie coat or undercoat and a composite topcoat. The coating thickness ratio of the topcoat to the undercoat may vary with the desired effect and/or the elution system. Typically these are of different formulations.
The coating may be applied by dipping or spraying using evaporative solvent materials of relatively high vapor pressure to produce the desired viscosity and quickly establish coating layer thicknesses. The preferred process is predicated on reciprocally spray coating a rotating radially expanded stent employing an air brush device. The coating process enables the material to adherently conform to and cover the entire surface of the filaments of the open structure of the stent but in a manner such that the open lattice nature of the structure of the braid or other pattern is preserved in the coated device.
The coating is exposed to room temperature ventilation for a predetermined time (possibly one hour or more) for solvent vehicle evaporation. Thereafter the polymeric precuser material is cured at room temperature or elevated temperatures or the solvent evaporated away from the dissolved polymer as the case may be. Curing is defined as the process of converting the elastomeric or polymeric material into the finished or useful state by the application of heat and/or chemical agents which include physical-chemical charges. Where, for example, polyurethane thermoplastic elastomers are used, solvent evaporation can occur at room temperature rendering the polymeric material useful for controlled drug release without further curing. Non-limiting examples of curing according to this definition include the application of heat and/or chemical agents and the evaporation of solvent which may induce physical and/or chemical changes.
The ventilation time and temperature for cure are determined by the particular polymer involved and particular drugs used. For example, silicone or polysiloxane materials (such as polydimethylsiloxane) have been used successfully. These materials are applied as pre-polymer in the coating composition and must thereafter be cured. The preferred species have a relatively low cure temperatures and are known as a room temperature vulcanizable (RTV) materials. Some polydimethylsiloxane materials can be cured, for example, by exposure to air at about 90xc2x0 C. for a period of time such as 16 hours. A curing step may be implemented both after application of a certain number of lower undercoat layers and the topcoat layers or a single curing step used after coating is completed.
The coated stents may thereafter be subjected to a postcure sterilization process which includes an inert gas plasma treatment, and then exposure to gamma radiation, electron beam, ethylene oxide (ETO) or steam sterilization may also be employed.
In the plasma treatment, unconstrained coated stents are placed in a reactor chamber and the system is purged with nitrogen and a vacuum applied to about 20-50 mTorr. Thereafter, inert gas (argon, helium or mixture of them) is admitted to the reaction chamber for the plasma treatment. A highly preferred method of operation consists of using argon gas, operating at a power range from 200 to 400 watts, a flow rate of 150-650 standard ml per minute, which is equivalent to about 100-450 mTorr, and an exposure time from 30 seconds to about 5 minutes. The stents can be removed immediately after the plasma treatment or remain in the argon atmosphere for an additional period of time, typically five minutes.
After the argon plasma pretreatment, the coated and cured stents are subjected to gamma radiation sterilization nominally at 2.5-3.5 Mrad. The stents enjoy full resiliency after radiation whether exposed in a constrained or non-constrained status. It has been found that constrained stents subjected to gamma sterilization without utilizing the argon plasma pretreatment lose resiliency and do not recover at a sufficient or appropriate rate.
The elastomeric material that forms a major constituent of the stent coating should possess certain properties. It is preferably a suitable hydrophobic biostable elastomeric material which does not degrade and which minimizes tissue rejection and tissue inflammation and one which will undergo encapsulation by tissue adjacent to the stent implantation site. Polymers suitable for such coatings include silicones (e.g., polysiloxanes and substituted polysiloxanes), polyurethanes (including polycarbonate urethanes), thermoplastic elastomers in general, ethylene vinyl acetate copolymers, polyolefin elastomers, EPDM ethylene-propylene terpolymer rubbers and polyamide elastomers. The above-referenced materials are considered hydrophobic with respect to the contemplated environment of the invention.
Agents suitable for incorporation include antithrobotics, anticoagulants, antiplatelet agents, thrombolytics, antiproliferatives, antinflammatories, agents that inhibit hyperplasia and in particular restenosis, smooth muscle cell inhibitors, antibiotics growth factors, growth factor inhibitors, cell adhesion inhibitors, cell adhesion promoters and drugs that may enhance the formation of healthy neointimal tissue, including endothelial cell regeneration. The positive action may come from inhibiting particular cells (e.g., smooth muscle cells) or tissue formation (e.g., fibromuscular tissue) while encouraging different cell migration (e.g., endothelium) and tissue formation (neointimal tissue).
The preferred materials for fabricating the braided stent include stainless steel, tantalum, titanium alloys including nitinol (a nickel titanium, thermomemoried alloy material), and certain cobalt alloys including cobalt-chromium-nickel alloys such as ELGILOY(copyright) and PHYNOX(copyright). Further details concerning the fabrication and details of other aspects of the stents themselves, may be gleaned from the above referenced U.S. Pat. Nos. 4,655,771 and 4,954,126 to Wallsten and 5,061,275 to Wallsten et al. To the extent additional information contained in the above-referenced patents is necessary for an understanding of the present invention, they are deemed incorporated by reference herein.
Various combinations of polymer coating materials can be coordinated with biologically active species of interest to produce desired effects when coated on stents to be implanted in accordance with the invention. Loadings of therapeutic material may vary. The mechanism of incorporation of the biologically active species into the surface coating, and egress mechanism depend both on the nature of the surface coating polymer and the material to be incorporated. The mechanism of release also depends on the mode of incorporation. The material may elute via interparticle paths or be administered via transport or diffusion through the encapsulating material itself.
For the purposes of this specification, xe2x80x9celutionxe2x80x9d is defined as any process of release that involves extraction or release by direct contact of the material with bodily fluids through the interparticle paths connected with the exterior of the coating. xe2x80x9cTransportxe2x80x9d or xe2x80x9cdiffusionxe2x80x9d are defined to include a mechanism of release in which a material released traverses through another material.
The desired release rate profile can be tailored by varying the coating thickness, the radial distribution (layer to layer) of bioactive materials, the mixing method, the amount of bioactive material, the combination of different matrix polymer materials at different layers, and the crosslink density of the polymeric material. The crosslink density is related to the amount of crosslinking which takes place and also the relative tightness of the matrix created by the particular crosslinking agent used. This, during the curing process, determines the amount of crosslinking and so the crosslink density of the polymer material. For bioactive materials released from the crosslinked matrix, such as heparin, a crosslink structure of greater density will increase release time and reduce burst effect.
Additionally, with eluting materials such as heparin, release kinetics, particularly initial drug release rate, can be affected by varying the average dispersed particle size. The observed initial release rate or burst effect may be substantially reduced by using smaller particles, particularly if the particle size is controlled to be less than about 15 microns and the effect is even more significant in the particle size range of xe2x89xa610 microns, especially when the coating thickness is not more than about 50 xcexcm and drug loading is about 25-45 weight percent.
It will also be appreciated that an unmedicated silicone thin top layer provides an advantage over drug containing top coat. Its surface has a limited porosity and is generally smooth, which may be less thrombogeneous and may reduce the chance to develop calcification, which occurs most often on the porous surface.